Recent years have witnessed an increase in the number of patients, and their age, with diminished immune function due to advanced chemotherapy and the sort, so there has been increasing importance placed on how to deal with opportunistic infection. As indicated by the fact that opportunistic infections are increasingly being caused by different attenuated viruses, the problem of infection will not go away as long as there is a basic disease that lowers the resistance of a patient. Therefore, a new way of dealing with infection that includes the problem of drug resistance is being viewed as one of the most important issues facing our aging society that looms near on the horizon.
In the field of antifungal agents, in the past, for example, polyene-based amphotericin B, azole-based fluconazole, itraconazole, voriconazole, and the like have been developed for treatment of latent fungal infections. Most of the existing drugs already on the market have a similar mechanism, and the appearance of azole-resistant fungi and so forth is currently becoming a problem.
Cyclic hexapeptide-based caspofungin, micafungin, and the like based on natural substances have been developed in recent years as 1,3-β-glucan synthetase enzyme inhibitors with a novel mechanism, but these pharmaceuticals can only be administered by injection, so they are still not satisfactory as an antifungal agent.
Under these situations, in which existing antifungal agents are inadequate, there is a need for the development of a safe pharmaceutical based on a novel mechanism. Related art relating to antifungal agents based on such a novel mechanism include Patent Documents 1 and 2. Patent Documents 1 and 2 describe pyridine derivatives that exhibit an effect against the onset, progress, and persistence of infection, by inhibiting the process of transport of GPI (glycosylphosphatidyl-inositol) anchor proteins to the cellular wall and thereby inhibiting the onset of cellular wall surface-layer proteins, inhibiting the onset of cellular wall assembly, and inhibiting the adhesion of fungi to cells, so that the pathogen cannot manifest its pathogenicity.
However, the compound groups disclosed in Patent Document 1 have a 2-benzylpyridine as a common structure, and are clearly different structurally from the compounds according to the present invention. Furthermore, a problem with the compound groups disclosed in Patent Document 1 is that, although they exhibit activity in vitro, they are readily metabolized in the body. Also, while the compound groups disclosed in Patent Document 2 exhibit excellent antifungal activity, they have the structure represented by the following formula:
and even with compounds having a pyridine ring skeleton, said compound groups are clearly different structurally from the compounds according to the present invention in that their common structure is that they are bonded with a monocycle at the 3-position of the pyridine ring, using an amidomethylene group as a linker.
Patent Documents 3 to 5 are examples of prior art that is structurally similar to the compounds according to the present invention. Patent Document 3 describes a pyridine derivative substituted with a tetrazole ring, which is used as an anticancer agent based on the inhibitory action of a lyase enzyme; Patent Document 4 describes a pyridine derivative substituted with a triazole ring, which is used as an NK-1 receptor antagonist; and Patent Document 5 describes a pyridine derivative substituted with a tetrazole ring, which is used to treat chronic rheumatoid arthritis or degenerative arthritis, based on the inhibitory action of matrix metalloproteinase.
However, Patent Documents 3 to 5 do not describe the compounds according to the present invention, and Patent Documents 3 to 5 disclose nothing whatsoever regarding any antifungal action against Candida, Aspergillus, Cryptococcus, or other such fungi that are common in human fungal infection.
Patent Document 1: International Publication Pamphlet 02/04626
Patent Document 2: International Publication Pamphlet 05/033079
Patent Document 3: International Publication Pamphlet 03/027095
Patent Document 4: International Publication Pamphlet 03/091226
Patent Document 5: International Publication Pamphlet 04/014366